Download - Roche Analyst Event
51st ASCO Annual Meeting, Chicago
Roche Analyst Event Sunday, 31 May 2015
Agenda
Welcome Karl Mahler, Head of Investor Relations Oncology strategy and outlook Daniel O’Day, Chief Operating Officer, Roche Pharmaceuticals Working along the cancer immunity-cycle: Strategies and new agents Ira Mellman, gRED: Ph.D., Vice President, Cancer Immunology, Genentech William Pao, pRED: M.D., Ph.D., Global Head Oncology Discovery and Translational Area, Roche ASCO 2015 Roche highlights: Setting new standards, developing combinations Sandra Horning, M.D., Chief Medical Officer and Head Global Product Development Growing importance of molecular information in cancer immunotherapy Garret Hampton, Ph.D., Vice President, Oncology Biomarker Development and Companion Diagnostics Summary and Q&A Karl Mahler, Head of Investor Relations
2
Oncology strategy and outlook
Daniel O’Day Chief Operating Officer, Roche Pharmaceuticals
3
Roche oncology: Continued sales growth A portfolio of differentiated medicines
4
CHF m
Sales at 2014 average exchange rates
0 2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 2001 2000 1999 1998
24,000
16,000 18,000
14,000
22,000 20,000
12,000 10,000 8,000
6,000 4,000 2,000
10 medicines 16 tumor types 42 indications
Oncology continues to become more complex Science, clinical practice evolving with understanding of disease biology
5
KRAS EGFR
Unknown
Classification of lung adenocarcinomas
>1 mutated gene 3% MEK1 <1%
NRAS 1% MET 1% PIK3CA
1% BRAF 2% HER2 3%
EGFR (other) 4%
ALK 8% EGFR
17%
KRAS 25%
No oncogenic driver detected
35%
2014 2004 Today
Com
plex
ity
PD-L1 positive (illustrative)
Pao & Girard. Lancet Oncol 2011; Johnson, et al. ASCO 2013
Roche’s oncology strategy has remained constant Today’s presentations highlight the results of our strategy across key programs
Personalized healthcare
• Differentiation via biomarkers
• Experts integrated in R&D
Higher certainty of patient benefit: Better for patients and for reimbursement
6
Follow the science
• Bringing our best minds together
• Science driven programs
Strong portfolio & development
• Comprehensive pipeline and active partnering
• Smart trial design
7
Strategy in action - Immunotherapy
Perspectives in key franchises
Summary
Strategy into action: Learning loop Comprehensive and scientifically driven strategies – crafted by our best minds
• Ideation
• Decision making
• Quick & efficient pursuit of promising ideas
...and we dedicate budget for rapid proof of concept
studies (Ph1)
8
Research (gRED, pRED, Chugai &
external)
Development (early and late)
Clinical Insights & Biomarkers (internal and external)
Partnering (Genentech and Roche)
We bring our best scientists & clinicians
together for:
Immunotherapy & Combinations
Atezolizumab (aPD-L1, MPDL3280A) strategy Biomarker selection and combinations
Our vision: Bringing the potential for transformative benefit to a broad patient population either in mono therapy or combinations
Diagnostic selection to identify patients most likely to benefit from
atezolizumab as a monotherapy
Improve survival using well-tolerated combinations with existing and
emerging therapies
PD-L1+ (tumor – infiltrating
immune cells)
PD-L1+ (tumor cells)
9
Atezolizumab in 2/3L NSCLC (POPLAR) Clinical outcomes correlate with PD-L1 expression
10
Overall Survival
TC2/3 or IC2/3 37%*
TC0 and IC0 32%*
TC1/2/3 or IC1/2/3 67%*
TC3 or IC3 16%*
0 0.5 1 1.5
0.46
0.63
1.12
0.56
1.93
HRa
In favor of docetaxel In favor of atezolizumab
0 0.5 1 1.5
0.57
0.87
1.17
0.70
1.87
HRa
In favor of docetaxel In favor of atezolizumab
Progression Free Survival
a = Unstratified HR; * = eligible patient population Spira A. et al, ASCO 2015
ITT n=287 0.98 0.77
Atezolizumab strategy: Combinations Scientifically driven strategy that combines with chemo, targeted therapy, and other immunotherapy
11
Checkpoint Inhibitors Anti-PD-L1, Anti-TIGIT, IDOi, Anti-OX40
Eliminate M2 Macrophages Anti-CSF-1R
pRED gRED
Tumor-targeted cytokines Anti-CEA-IL2v FP Anti-FAP-IL2v FP APC stimulators
Anti-CD40 (agonist)
Costimulatory antibodies Anti-OX40 (agonist) T cell bispecifics
Anti-CEA/CD3 TCB
Both
Priming & activation
Antigen presentation
Antigen release
T cell infiltration
T cell Trafficking
Cancer T cell recognition
T cell killing
Clinical phase molecules
Chen & Mellman (2013) Immunity
Atezolizumab strategy: Programs by disease
LUNG 2L+ single-arm
Ph2 (x2) 2L+ rand Ph2 and
rand Ph3 1L single-agent
Ph3 (x2) 1L w/chemo,
Avastin Ph3 (x3)
BLADDER 2L+ & 1L cis-inel
single-arm Ph2
2L+ rand Ph3
Adjuvant Ph3 BREAST
1L w/Abraxane Ph3
KIDNEY
1L w/Avastin Ph2
1L w/Avastin Ph3
15 Roche / Genentech Phase 2 or 3 Studies
12
Focused strategy: Going deep in diseases where we have strong scientific rationale
Atezolizumab strategy: Summary Comprehensive, science-driven program
Immune Doublets Examples: • Loc adv/ metastatic solid tumors with
ipilimumab or Interferon alfa-2b (Ph Ib) • Combination with anti-CSF-1R (Ph Ib) • Combination with anti-CD40 (Ph Ib) • Combination with Incyte’s IDOi (Ph Ib) • Combination with anti-OX40 (Ph Ib) • Combination with CEA-IL2v (Ph Ib) • Combination with Celldex anti-CD27
Dx + Monotherapy Examples: • mRCC (Ph II) • mUBC (Ph II) • 2L mNSCLC (Ph II ‘BIRCH’, ‘POPLAR’, ‘FIR’,
Ph III ‘OAK’) • Dx+ 1L NSCLC (2x: Sq/NSq, Ph III) • Dx+ mUBC (Ph III)
Combination with Chemotherapy
Examples: • 1L NSCLC Squamous and Non-
Squamous with platinum doublets (x3, Ph III)
• 1L TNBC with Abraxane (Ph III)
Combination with Targeted Therapy
Examples: • mRCC with Avastin (Ph II) • mRCC with Avastin (Ph III) • EGFR+ NSCLC w/Tarceva (Ph Ib) • ALK+ NSCLC w/alectinib (Ph Ib) • Solid tumors with Avastin (Ph Ib) • Solid tumors w/cobimetinib (Ph Ib) • Lymphoma with Gazyva (Ph Ib)
Strategic pillars of our PD-L1 development approach
Immune Doublets
Chemotherapy Combinations
13
Dx+ Monotherapy
Targeted Therapy
Combinations
14
Strategy in action - Immunotherapy
Perspectives in key franchises
Summary
Hematology strategy on track Strong pipeline and programs across key indications
15
Compound Combination Indication P 1 P 2 P 3
Gazyva +chemo GREEN CLL
Gazyva +chemo GOYA aNHL
Gazyva +chemo GADOLIN iNHL
Gazyva +chemo GALLIUM 1L FL
Gazyva +aPD-L1 R/R FL
Gazyva +aPD-L1 aNHL
venetoclax* +Rituxan MURANO R/R CLL
venetoclax +Gazyva CLL14 CLL
venetoclax R/R CLL 17p
venetoclax +Rituxan/+BR R/R FL
venetoclax +Rituxan/Gazyva+chemo 1L aNHL
venetoclax +BR R/R NHL
venetoclax +bortezomib+chemo R/R MM
venetoclax +chemo AML
polatuzumab +Rituxan/Gazyva ROMULUS NHL
polatuzumab +Gazyva/BR R/R FL
polatuzumab +Gazyva/BR aNHL
Biosimilars delayed to 2017
Data presented at ASCO
* venetoclax in collaboration with AbbVie BR = bendamustine+Rituxan venetoclax (Bcl2 inhibitor); polatuzumab vedotin (CD79b ADC)
HER2 franchise outlook Complete portfolio of innovative drugs
16
2017
Established standard of care New standard of care Trials in progress
Adjuvant BC
Herceptin + chemo
Herceptin sc + chemo (HannaH)
Herceptin & Perjeta + chemo (APHINITY)
1st line mBC
Herceptin + chemo
Herceptin & Perjeta + chemo (CLEOPATRA)
2nd line mBC Xeloda + lapatinib Kadcyla (EMILIA)
2016 2012 2013 2014 2015 2011 2019 2018 2020
Kadcyla (KATHERINE) Kadcyla & Perjeta (KAITLIN)
Biosimilar launch (EU)
Neoadjuvant BC
Herceptin + chemo (NOAH)1
Herceptin & Perjeta + chemo (Neosphere, Tryphaena)
Kadcyla & Perjeta (KRISTINE)
Kadcyla & Perjeta (MARIANNE)
HER2 franchise: Perjeta commercial uptake strong
1,600
1,800
2,000
2,200
0 Q1 Q4 Q2 Q3 Q4 Q1 Q3
Perjeta Herceptin
Kadcyla
2014 2015 2013
Perjeta US Neoadj Approval
Perjeta Cleopatra
OS Readout
Next Milestone: eBC readout (APHINITY) in 2016
NEOSPHERE OS Data at this
ASCO CHFm
17
Avastin franchise Continues to be the most studied molecule at ASCO
Continued growth fueled by recent launches in cervical, ovarian cancers
Avastin Mesothelioma data presented at ASCO 2015
18
0
1,000
2,000
3,000
4,000
5,000
6,000
7,000
2011 2012 2013 2014
CHFm
Sales at 2014 average exchange rates
19
Strategy in action - Immunotherapy
Perspectives in key franchises
Summary
Collaborations: Zelboraf with Plexxikon; Cobimetinib iwith Exelixis; Alectinib with Chugai, Gazyva with Biogen Idec; Kadcyla with ImmunoGen
ASCO 2015: Roche highlights
• More than 275 abstracts, Avastin most quoted drug
• Potential improvements on current standard of care: – Cobimetinib / Zelboraf in 1L skin cancer (targeted therapies) – Alectinib in 2L ALK mutated lung cancer
• New treatment options: – Atezolizumab in 2L lung cancer (vs chemo) – Atezolizumab combinations with chemo in lung and TNBC – Avastin in mesothelioma – Gazyva in R/R indolent NHL
• Several filings resulting from data presented at the meeting
20
Roche’s oncology strategy has remained constant Today’s presentations highlight the results of our strategy across key programs
Personalized healthcare
• Differentiation via biomarkers
• Experts integrated in R&D
Higher certainty of patient benefit: Better for patients and for reimbursement
21
Follow the science
• Bringing our best minds together
• Science driven programs
Strong portfolio & development
• Comprehensive pipeline and active partnering
• Smart trial design
Working along the cancer immunity-cycle: Strategies and new agents I
22
Ira Mellman Vice President, Cancer Immunology, Genentech
The renaissance of immunotherapy is a revolution for cancer patients
23
Early data suggests that anti-PD-L1/PD-1 is active across a wide range of tumor types
Broad activity but only subset of patients benefit
ORR ~10-30% Melanoma
Bladder cancer
Head & Neck cancer
Breast cancer
Hodgkin’s lymphoma
Lung cancer
Renal cancer
Most patients will need biomarker selection and combination therapy: Strategy now supported by clinical results
Using patient data to understand cancer immunity-cycle
Progressive disease (PD) Why do many patients not respond? • No pre-existing immunity?
Cha
nge
in s
um o
f lon
gest
dia
met
ers
(SLD
) fr
om b
asel
ine
(%)
100 80 60 40 20 0
-20 -40 -60 -80
-100 0 21 42 63 84 105 126 147 168 189 210 231 252 273 294
Time on study (days)
Complete response Partial response Stable disease Progressive disease
Monotherapy durable responses (PR/CR) What are the drivers of single agent response? How can PRs be enhanced to CRs? • Insufficient T cell immunity? • Multiple negative regulators?
Stable disease (SD) What combinations will promote PRs & CRs? • Insufficient T cell immunity? • Multiple negative regulators?
Powles et al., Nature 2014
Atezolizumab Phase 1 data: Urothelial bladder cancer patients
Combinations of immunotherapeutics Increasing response rates & benefit by keeping cancer immunity-cycle turning
26 Chen & Mellman (2013) Immunity
Genentech/Roche programs *Partnered programs
1
2
3
4
5
6
7
Cancer antigen presentation
(dendritic cells/APCs)
Priming and activation (APCs & T cells)
Trafficking of T cells to tumors
(CTLs)
Infiltration of T cells into tumors
(CTLs, endothelial cells)
Recognition of cancer cells by T cells (CTLs, cancer cells)
Killing of cancer cells (Immune and cancer cells)
Release of cancer cell antigens (Immune and cancer cells)
Avastin®
vaccines Anti-CD40
Anti-OX40 Anti-CD27* Anti-CTLA4*
Anti-PD-L1/PD-1 Anti-TIGIT Anti-OX40 (Treg)
Anti-CSF-1R IDO inhibitor Anti-CEA-IL2v
T cell bispecifics ImmTacs
IDO (indoleamine di-oxygenase) A suppressor of effector T cells
IFNg-mediated up-regulation of
tumor PD-L1
Shp-2
MAPK"PI3K
pathways"
IFNg-mediated up-regulation of
tumor IDO
Kynurenine Tryptophan
Shp-2
MAPK"PI3K
pathways"
Adaptive expression of PD-L1 Adaptive expression of IDO
IDO
T cell suppression
Pre-clinical data shows promising activity for IDO inhibition (GDC-0919)
28
• Plasma kynurenine decrease
• T regulatory cells decrease
• T effector cells show increased proliferation & CTL function
• Enhanced anti-tumor efficacy with anti-PD-L1 and anti–CTLA4
Anti-PD-L1 + IDOi
IDOi Anti-PD-L1 control
Ongoing studies • Phase 1a (GDC-0919) • Phase 1b combination (GDC-0919 + atezolizumab) • Phase 1b combination (INCB024360 + atezolizumab)
Tum
or v
olum
e (m
m3 )
500
1000
1500
2000
Day
0 40 30 50 20 10 0
GDC-0919 in collaboration with NewLink; INCB024360 in collaboration with Incyte
TIGIT A second potent negative regulator of T cell responses
29
Tumor cell or DC
PVR
ITIM
100nm 1nm
TIGIT CD226
ITIM ITAM
2
T cell
3
1
Competes with CD226 for PVR
Disrupts CD226 activation
Directly inhibits T cells in cis
1
2
3
• Human and murine tumor-infiltrating CD8+ T cells express high levels of TIGIT
• Antibody co-blockade of TIGIT and PD-L1 elicits tumor rejection in preclinical models
• TIGIT selectively limits the effector function of chronically stimulated CD8+ T cells
• TIGIT interacts with CD226 in cis and disrupts CD226 homodimerization
TIGIT=T cell immunoreceptor with Ig and ITIM domains
TIGIT aTIGIT and aPD-L1 combination effective in PD-L1 non-responsive model
30
Tumor cell or DC
PVR
ITIM
100nm 1nm
TIGIT CD226
ITIM ITAM
2
T cell
3
1
Competes with CD226 for PVR
Disrupts CD226 activation
Directly inhibits T cells in cis
1
2
3
TIGIT
Anti-PD-L1 + TIGIT
Control Anti-PD-L1
10000
1000
100
10 0 10 20 30 40 60
Day
Med
ian
tum
or v
olum
e (m
m3 )
Complete remission (CR)
31
Elevated expression of TIGIT by T cells in human cancer supports combination with atezolizumab
Johnson et al (2014) Cancer Cell
TIGI
T/CD
3ε ra
tio
0.05
0.5
0.2
0.1
1.00
CD3ε
50
200
1000
5000
2 10 50 500
Tumor Normal
ρ=0.82
Lung squamous cell carcinoma
TIGIT
OX40 exhibits a dual mechanism of action Promote antigen dependent effector T cell activation and T regulatory cell inhibition
32
Effector T cell
TCR
Antigen Presenting Cell
OX40
OX40L
IFN-γ
OX40 engagement on Treg cells
Treg
OX40L
OX40L
OX40
Primary Tumor Challenge (EMT6)
10 0 20 30 40 50 0
1000
2000
3000
Tum
or v
olum
e (m
m3 )
Day
Control
Anti-mouse OX40
Adapted from Nature Rev Immunol. 4:420 (2004)
Increase in T effector cells by aOX40 may create need to combine with aPD-L1
anti-OX40
anti-PD-L1 (or IDOi)
PD-L1 increase
IFN-γ"
OX40L
OX40
CD8 T cell receptor
HLA
PD-1
PD-L1
Tumor cell
T cell
IFNγ
Promising pre-clinical efficacy of an aOX40/aPD-L1 combination model
0 20 40 600
500
1000
1500
2000
2500
day
Tum
or V
olum
e (m
m3 ) anti%PD%L1*
control*
Day 0 10 20 30 40 50
0
500
1000
1500
2000
2500
day
Tum
or V
olum
e (m
m3 ) !!!!!!!!!!!!!!!!!!!!!!!anti&OX40!
!!!!!!!!!!!!!!!!!control!
Tum
or v
olum
e (m
m3 )
Tum
or v
olum
e (m
m3 )
Day
anti-OX40 control
anti-PD-L1 control
0 20 40 600
500
1000
1500
2000
2500
day
Tum
or V
olum
e (m
m3 )
anti%OX40*+*anti%PD%L1*
Tum
or v
olum
e (m
m3 )
Day
anti-OX40 + anti-PD-L1
Jeong Kim et al. AACR 2015
Ongoing studies • Phase 1a (MOXR0916)
• Phase 1b combination (MOXR0916 + atezolizumab)
• Planned (MOXR0916 + GDC-0919)
MOXR0916 = anti-OX40
Combinations with chemotherapy Induced inflammation & antigen release may enhance atezolizumab efficacy
35
Chemotherapy Vaccines
1
2
3
4
5
6
7
Cancer antigen presentation
(dendritic cells/APCs)
Priming and activation (APCs & T cells)
Trafficking of T cells to tumors
(CTLs)
Infiltration of T cells into tumors
(CTLs, endothelial cells)
Recognition of cancer cells by T cells (CTLs, cancer cells)
Killing of cancer cells (Immune and cancer cells)
Release of cancer cell antigens (Immune and cancer cells)
Chen & Mellman (2013) Immunity
Combinations may extend the benefit of aPD-L1 Preclinical synergy with selected chemo and targeted therapies
Dosing
0
500
1000
1500
2000
2500
3000
0 6 12 16 22 29 36
Tum
or V
olum
e, m
m3
Day
aPD-L1
combo
Control
CT26 08-1033O
0 10 20 30 40 500
500
1000
1500
2000
2500
DayTu
mor
Vol
ume
(mm
3)
controlGDC-0973 (7.5mg/kg)aPDL1GDC-0973 (3mg/kg) + aPDL1
MEKi
CT26 (Krasmut)
Dosing
Control aPD-L1
aPD-L1/ MEKi
Oxaliplatin chemotherapy MEKi targeted therapy
Tum
or v
olum
e, m
m3
Tum
or v
olum
e, m
m3
Oxaliplatin
-100
Combinations with chemotherapy appear to extend the benefit of atezolizumab in NSCLC patients
Liu et al. ASCO 2015
Chemotherapy can promote Th1-type inflammation in tumors
0 42 84 126 168 210 252 294 0 42 84 126 168 210 252 294
Time on study (days)
Chan
ge in
Sum
of L
arge
st D
iam
eter
s fro
m B
asel
ine
(%)
0 42 84 126 168 210 252 294 336
CR/PR (n=3) SD (n=2) PD (n=0)
CR/PR (n=9) SD (n=1) PD (n=1)
-90 -80 -70 -60 -50 -40 -30 -20 -10
10 20 30 40 50 60 70 80 90
100
0
Atezolizumab + carboplatin/paclitaxel
Atezolizumab + carboplatin/pemetrexed
Atezolizumab + carboplatin/nab-paclitaxel
CR/PR (n=8) SD (n=4) PD (n=1)
Strategic vision: Lead by developing best-in-class combination therapies
Combinations with immunotherapies aCD40 ✔ Vaccines, Oncolytic Viruses ✔ ✔ aCTLA4 ✔ aOX40 ✔ aCD27 ✔ aCEA/FAP-IL2v ✔ T Cell Bispecifics ✔ ImmTACs Planned IDOi ✔✔ aCSF1R ✔ aTIGIT Planned Cytokines, anti-cytokines ✔ Combinations with other agents aVEGF ✔ EGFRi ✔ ✔ ALKi Planned BRAFi ✔ MEKi ✔ BTKi ✔ aCD20 ✔ aHER2 ✔ Chemo ✔ ✔ HDAC ✔ A2V ✔
Internal combo ✔ ✔
Partnered external combo
1
2
3
4
5
6
7
Priming & activation anti-CEA-IL2v anti-FAP-IL2v anti-OX40 anti-CTLA4* anti-CD27* anti-cytokine
Antigen presentation anti-CD40 IMA942 vaccine* oncolytic viruses* neo-epitope vaccine
Antigen release Pro-inflammatory EGFRi ALKi BRAFi MEKi Chemo BTKi HDAC
T cell infiltration anti-VEGF anti-Ang2/VEGF
Cancer cell recognition anti-CEA/CD3 TCB anti-CEA-IL2v FP anti-HER2/CD3 anti-CD20/CD3 anti-FAP-IL2v FP ImmTAC*
Cancer cell killing atezolizumab anti-OX40 anti-CSF-1R IDOi* anti-TIGIT IDO/TDO TDO
T cell trafficking
Clinical development Preclinical development
* Partnered projects
Immuno- suppression
Working along the cancer immunity-cycle: Strategies and new agents II
William Pao, M.D., Ph.D. Global Head Oncology Discovery and Translational Area, Roche pRED
39
Cancer immunotherapy at pRED Distinct MoAs with potential for combinations
Designed to amplify immune response
First anti-tumor T-cell engager from Roche to enter clinical trials
Best/first in class immuno-activating Ab
First antibody shown to eliminate tumor- associated macrophages
Macrophage
aCEA-IL2v FP aCEA/CD3 TCB aCD40 aCSF-1R
40
Proof of biological activity established in rare disease (PVNS)
Novel recombinant immunocytokine with superior safety, PK, and tumor targeting
Best-in-class TCB platform
Activates antigen pre- senting cells to jumpstart adaptive immunity
Tumor-associated macrophages A promising new target in oncology
41
Emactuzumab (aCSF-1R) Proof of biological activity shown in PVNS*
*PVNS - pigmented villonodular synovitis, emactuzumab = anti-CSF-1R (RG7155)
CSF1R Inhibition with Emactuzumab in Locally Advanced Diffuse-type Tenosynovial Giant Cell Tumors of the soft tissue: a phase 1, dose escalation and expansion study, Cassier P. et al. (2015), Lancet Oncology, in press
Emactuzumab Phase I data: PVNS
Chan
ge in
sum
of l
onge
st d
iam
eter
s
from
bas
elin
e %
Time from baseline (days)
Patients %
Objective response 24/28 86
Complete response 2/28 7
Partial metabolic response 24/26 92
Clinically progression-free 27/28 96
Clinical benefit
Each color represents a patient
42
Emactuzumab: Elimination of tumor-associated macrophages in solid tumors – phase I data
43 atezolizumab = anti-PD-L1 (MPDL3280A) Gomez-Roca, CA: Phase I study of RG7155, a novel anti-CSF1R antibody, in patients with advanced/metastatic solid tumors, 2015 ASCO
Oral presentation on Mon 1 Jun; abstract #3005
• Proof of biological activity in wide range of tumor types • Potentially synergistic with atezolizumab
• Phase I combination study: dose escalation with atezolizumab ongoing • No severe immune-related AE reported to date • Multiple extensions to start Q3 2015
RG7155 plus Paclitaxel RG7155 monotherapy
% C
hang
e fro
m b
asel
ine
mac
roph
age
cov
erag
e (IH
C)
Depletion of CSF-1 dependent macrophages in solid tumors
Macrophages suppress T cell proliferation in vitro
Tumor targeted IL2v cytokine fusion proteins A platform to amplify and activate immune effectors in tumors
Mechanism of Action
Features
“IL-2v”
IL2v – interleukin-2 variant
Novel tumor-targeted, engineered IL-2 variant (IL-2v)-based immunocytokines for immunotherapy of cancer: Christian Klein et al., ASH, 2013, Blood 122 (21), 2278-2278
44
• Binds to target to deliver novel variant of IL-2 to the tumor
• Recruits killer T and Natural Killer (NK) cells to the tumor
• Compared to standard IL-2-based therapy, it shows:
− Superior expansion of immune effectors
− Less activation of suppressive T-cells
− Better tolerability
− Better tumor targeting
aCEA-IL2v – phase I data Tumor targeting and intra-tumoral T cell activation
CEA - carcinoembryonic antigen; *Quantitative data from 2 CEA-ve patients pending, no tumor uptake on visual assessment *Schellens, Jan H. M. et al., CEA-targeted engineered IL2: Clinical confirmation of tumor targeting and evidence of intratumoral immune activation; 2015 ASCO
Increased CD8 densities and CD8:CD4 ratio confirm intra-tumoral immune activation at doses ≥ 20 mg
CD8
dens
ity (c
ells/
mm
2 )
aCEA-IL2v is an ideal combination partner for atezolizumab: Phase I combination starting
baseline (BL) 4d p.1. CEA-IL2v dose baseline (BL) 4d p.1. CEA-IL2v dose
CD8:
CD4
Ratio
45
Oral poster presentation on Saturday 30 May; abstract # 3016*
CEA-IL2v tumor accumulation shown in 4/4 patients with CEA+ tumors
89Zr-CEA-IL2v-PET/CT
Baseline
CEA
+ve
N
SCLC
C
RC
C1D5 C1D2
FDG-PET/CT
aFAP-IL2v: A complementary approach targeting tumor stroma
FAP – fibroblast-activation protein
FAP staining
• FAP-IL2v phase I start: planned in 2015
Parameter CEA-IL2v FAP-IL2v Target cell Cancer cells
(CEA) Tumor stromal cells (FAP)
Target expression
Heterogeneous Homogeneous
Target density Medium High Indications Mainly GI
indications: GC, PaC, CRC
Very broadly expressed: High expression in e.g. H&N, sq NSCLC, BC
46
BITE
ü High interest, outstanding clinical efficacy with CD19 CARs in hematology
û Activity associated with high toxicity
û Challenging manufacturing and regulatory processes
Potency üüü ü üüü Long half-life û üüü üüü Differentiation of high vs low antigen expressing cells
ü ü üüü
“1:1” format
“2:1” format
T cell engaging therapies in development CAR T cells versus T cell bispecific antibodies
47
Engineered T cells (CARS) T cell engaging bispecific antibodies
CEA-TCB: First “ 2:1” T cell bispecific in the clinic Targets CEA-expressing tumors to induce localized T cell-mediated killing
CD3e T cell engagement Low affinity
High avidity binding to tumor
antigen
Inert, engineered Fc region
48
Mechanism of Action
Features
• Binds T cells and tumor cells simultaneously • Results in T cell activation/proliferation and killing of tumor cells • Does not require MHC:peptide complex presentation by tumor
cells • T cell engagement independent of specificity and activation
status
• Entry into human – study started in Dec 2014 • Combination with IL2v & PD-L1 planned early in clinical
development • Broad, early pipeline of several TCBs addressing solid &
hematological malignancies
CEA-TCB: Novel mode of action From poorly inflamed to highly inflamed tumors
• Recruits new T cells and/or expands pre-existing ones • Induces T cell re-localization from tumor periphery to tumor bed • Activates intra-tumor T cells to become differentiated towards effector memory phenotype
49
Intravital two-photon imaging 24 h after CEA-CD3 therapy. Red: Tumor cells (LS174T RFP). Green: Human T cells
Control CEA-CD3
Bacac M. et al., submitted
Roche cancer immunotherapy pipeline
Abundant opportunities for combinations
Checkpoint Inhibitors Anti-PD-L1, Anti-TIGIT, IDOi, Anti-OX40
Eliminate M2 Macrophages Anti-CSF-1R
pRED gRED
Tumor-targeted cytokines Anti-CEA-IL2v FP Anti-FAP-IL2v FP APC stimulators
Anti-CD40 (agonist)
Costimulatory antibodies Anti-OX40 (agonist) T cell bispecifics
Anti-CEA/CD3 TCB
Both
Priming & activation
Antigen presentation
Antigen release
T cell infiltration
T cell Trafficking
Cancer T cell recognition
T cell killing
Clinical phase molecules
50 Chen & Mellman (2013) Immunity
Cancer immunotherapy program growing strongly
51
Compound Combination Indication Phase 1 Phase 2 Phase 3
aPD-L1
Mono +Tarceva +chemo +Avastin+chemo
Lung cancer
aPD-L1 Mono Bladder cancer
aPD-L1 Mono +Avastin Renal cancer
aPD-L1 +Zelboraf +Zelboraf+cobimetinib Melanoma
aPD-L1
Mono +Avastin +cobimetinib +ipilimumab +IFN alfa-2b +aCD40 +aOX40 +aCSF-1R +aCEA-IL2v FP
aPD-L1 +Avastin+FOLFOX Colorectal cancer
aPD-L1 Mono +Gazyva Hematology
aPD-L1 Mono +chemo Triple neg. breast cancer
aCSF-1R Mono +aCD40 Solid tumors
aCEA-IL2v FP Mono Solid tumors
aFAP-IL2v FP Mono Solid tumors
aOX40 Mono Solid tumors
aCEA/CD3 TCB Mono Solid tumors
IDO Mono Solid tumors
IDO (Incyte)* +aPD-L1 Solid tumors
Varlilumab (Celldex)* +aPD-L1 Solid tumors
Study ongoing Study imminent * External collaboration
Solid tumors
52
ASCO 2015 Roche highlights: Setting new standards, developing combinations
Sandra Horning, M.D. Chief Medical Officer and Head Global Product Development
53
Cancer immunotherapy Roche program update Atezolizumab in lung cancer Atezolizumab in bladder cancer
Targeted therapies and combinations
Alectinib in ALK-positive lung cancer Cobimetinib + Zelboraf in melanoma Kadcyla, Perjeta, Herceptin in HER2+ breast cancer
Hematology Gazyva in NHL
Agenda Setting new standards, developing combinations
Roche cancer immunotherapy program
54
aPD-L1 NSCLC (Dx+)
aPD-L1 2/3L NSCLC
aPD-L1+Avastin 1L Renal aPD-L1
1/2L Bladder
Phase II Phase III Phase I aPD-L1
2/3L NSCLC aPD-L1**
2/3L Bladder aPD-L1+Avastin+chemo**
1L non sq NSCLC aPD-L1+chemo** 1L non sq NSCLC
aPD-L1+chemo** 1L sq NSCLC
aPD-L1** 1L non sq NSCLC (Dx+)
aPD-L1** 1L sq NSCLC (Dx+) aPD-L1+chemo**
1L TNBC
aPD-L1** Adjuvant MIBC (Dx+)
aPD-L1** tba
aPD-L1+Avastin** 1L RCC
Status as at May 31, 2015
IDO Solid tumors
aPD-L1+ipilimumab Solid tumors
aPD-L1+aCD40 Solid tumors
aPD-L1+IFN-alfa Solid tumors
aPD-L1+aCSF-1R** Solid tumors
aPD-L1+aCEA-IL2v FP** Solid tumors
aPD-L1+aOX40** Solid tumors
aPD-L1** tba
aPD-L1** tba
aPD-L1** tba
aPD-L1** tba
aPD-L1** tba
NME** tba
aPD-L1 trials
NMEs monotherapy
2015 readout expected
Study start in 2015
Immune doublets
**
üData at ASCO 2015
üü
aOX40 Solid tumors
aCEA/CD3 TCB Solid tumors
aPD-L1+Zelboraf Melanoma
aPD-L1+Tarceva NSCLC
aPD-L1+Avastin+chemo Solid tumors
aPD-L1 + Gazyva R/R FL / aNHL
aCSF-1R Solid tumors
aCEA-IL2v FP Solid tumors
aPD-L1+Avastin Solid tumors
aPD-L1+cobimetinib Solid tumors
aPD-L1+Zelboraf+cobi** Melanoma
aPD-L1+lenalidomide** MM
aPD-L1+chemo Solid tumors
aPD-L1 Solid tumors üü
ü
üü
Biomarker development for atezolizumab PD-L1 expression on different cell types
55
IC Score PD-L1 staining TC Score PD-L1 staining
IC3 IC ≥ 10% TC3 TC ≥ 50%
IC2 IC ≥ 5% and < 10% TC2 TC ≥ 5% and < 50%
IC1 IC ≥ 1% and < 5% TC1 TC ≥ 1% and < 5%
IC0 IC < 1% TC0 TC < 1%
PD-L1 expression on immune cells (IC) and tumor cells (TC)
Gettinger S. et al, ASCO 2015
Assessed by immunohistochemistry using SP142, a sensitive and specific proprietary monoclonal antibody assay against PD-L1
Tumor cell staining Immune cell staining
Atezolizumab clinical program in 2/3L NSCLC Breakthrough designation in PD-L1+ patients
56
ORR Data at ASCO
All comers 2/3L mNSCLC n=1100
PD-L1 stratified
atezolizumab
1200 mg IV Q3 weeks
docetaxel
75 mg/m2 IV Q3 weeks
OAK Phase III
OS Data expected 2016
PD-L1-selected mNSCLC n=138
atezolizumab
1200 mg IV Q3 weeks
POPLAR Phase II OS Interim data at ASCO Final data in H2 2015
All comers 2/3L mNSCLC n=287
PD-L1 stratified
atezolizumab
1200 mg IV Q3 weeks
docetaxel
75 mg/m2 IV Q3 weeks
BIRCH Phase II PD-L1-selected
mNSCLC n=667 atezolizumab
1200 mg IV Q3 weeks ORR Data in Q3 2015
Note: Atezolizumab (Anti-PD-L1) is listed as MPDL3280A in clinicaltrials.gov mNSCLC = metastatic Non Small-Cell Lung Cancer
Primary end-point: FIR Phase II
atezolizumab
1200 mg IV Q3 weeks
Atezolizumab in 2/3L NSCLC (POPLAR) Clinical outcomes correlate with PD-L1 expression
57
Overall survival
TC2/3 or IC2/3 37%*
TC0 and IC0 32%*
TC1/2/3 or IC1/2/3 67%*
TC3 or IC3 16%*
0 0.5 1 1.5
0.46
0.63
1.12
0.56
1.93
HRa
In favor of docetaxel In favor of atezolizumab
0 0.5 1 1.5
0.57
0.87
1.17
0.70
1.87
HRa
In favor of docetaxel In favor of atezolizumab
Progression-free survival
a = unstratified HR; * = eligible patient population Spira A. et al, ASCO 2015
ITT n=287 0.98 0.77
Atezolizumab in 2/3L NSCLC (POPLAR) Overall survival correlates with PD-L1 expression
58
• Final POPLAR and BIRCH read-outs in H2 15
• Phase III (OAK) in all comers (stratified by PD-L1 expression): Data in 2016
a = Unstratified HR Spira A. et al, ASCO 2015
9.1 mo (7.4, 12.8)
Not Reached (11.0, NE)
9.7 mo (6.7, 11.4)
9.7 mo (8.6, 12.0)
TC1/2/3 or IC1/2/3 TC0 or IC0
Atezolizumab + chemotherapy in 1L NSCLC (Ph1) Well tolerated with no unexpected toxicities
59
atezolizumab 15mg/kg IV q3w+ carboplatin q3w + nab-paclitaxel q1w
atezolizumab 15mg/kg IV q3w+ carboplatin q3w + pemetrexed q3w
atezolizumab 15mg/kg IV q3w+ carboplatin q3w + paclitaxel q3w
1L NSCLC n=37
E
D
C
4-6 cycles
atezolizumab
atezolizumab +/- pemetrexed
maintenance
Treat to PD or
loss of clinical benefit
Treat to PD or
loss of clinical benefit
Treat to PD or
loss of clinical benefit
atezolizumab
Liu S. et al, ASCO 2015
• The addition of atezolizumab to standard 1L chemotherapy was well tolerated throughout the course of treatment, including maintenance therapy, with no unexpected toxicities
• No autoimmune renal toxicity or pneumonitis was observed
Atezolizumab + chemotherapy in 1L NSCLC (Ph1) Efficacy unrelated to PD-L1 expression
60 ORR across all arms = 67% (48-82) CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease Liu S. et al, ASCO 2015
Arm C, n=5 Arm D, n=12 Arm E, n=13
-100
0 42 84 126 168 210 252 294 0 42 84 126 168 210 252 294
Time on study (days)
Chan
ge in
Sum
of L
arge
st D
iam
eter
s fro
m B
asel
ine
(%)
0 42 84 126 168 210 252 294 336
CR/PR (n=3) SD (n=2) PD (n=0)
CR/PR (n=9) SD (n=1) PD (n=1)
-90 -80 -70 -60 -50 -40 -30 -20 -10
10 20 30 40 50 60 70 80
0
CR/PR (n=8) SD (n=4) PD (n=1)
atezolizumab + carboplatin/paclitaxel
atezolizumab + carboplatin/pemetrexed
atezolizumab + carboplatin/nab-paclitaxel
ORR (95% CI)
60% (19-92)
75% (45-93)
62% (33-83)
90 100
Atezolizumab phase III program in 1L NSCLC Developing combinations, building on predictive PD-L1 biomarker
61
Study Indication Treatment arms Primary completion*
Combination studies – All comers (PD-L1 subgroup analysis)
GO29436 n=1200
Non-squamous Atezo + Carbo + Pac Atezo + Carbo + Pac + Avastin Carbo + Pac + Avastin
2017 (PFS)
GO29537 n=550
Non-squamous Atezo + Carbo + Nab-pac Carbo + Nab-pac 2017 (PFS)
GO29437 n=1200
Squamous Atezo + Carbo + Pac Atezo + Carbo + Nab-pac Carbo + Nab-pac
2017 (PFS)
Monotherapy studies – PD-L1 Selected
GO29431 n=400
Non-squamous Atezo Cis or Carbo + Pem 2017 (PFS)
GO29432 n=400
Squamous Atezo Cis or Carbo + Gem 2017 (PFS)
Atezo=atezolizumab; Carbo=Carboplatin; Pac=Paclitaxel; Nab-pac= Nab-paclitaxel; Cis=Cisplatin; Pem=Pemetrexed; Gem=Gemcitabine Note: Atezolizumab (Anti-PD-L1) is listed as MPDL3280A in clinicaltrials.gov `
* Outcome studies are event driven, timelines may change, OS endpoint included for all studies
Atezolizumab in 2L UBC (Ph1) ORR correlates with PD-L1 expression
62 UBC = urothelial bladder Cancer; IC = immune cells; ORR = overall response rate Petrylak D. et al, ASCO 2015
• Response rates correlate with PD-L1 status; 20% CR in IHC2/3 • Responses observed with visceral metastases: 38% RR in IHC2/3 • Well tolerated with 5% Gr3/4 immune-related adverse events
IC0 IC1 IC2 IC3
Atezolizumab responses by PD-L1 biomarker status
PD-L1 IHC n=87
ORR, % (95% CI)
IC3 (n=12) 67% (35, 90) 50% (35, 65)
IC2 (n=34) 44% (27, 62)
IC1 (n=26) 19% (7, 39) 17% (7, 32)
IC0 (n=15) 13% (2, 40)
Atezolizumab in 2L UBC (Ph1) Survival correlates with PD-L1 expression
63
Overall survival
• PD-L1 is a predictive biomarker for ORR, PFS and OS in 2L bladder cancer • Phase II study (NCT02108652) in 1/2L bladder: Read-out H2 2015 • Phase III studies in 2/3L bladder and high risk muscle invasive bladder after cystectomy (adjuvant)
started in 2015
Petrylak D. et al, ASCO 2015
7.6 mo (95% CI, 4.7-NE)
Not Reached (95% CI, 9.0-NE)
Survivala
N = 92 IC2/3 n = 48
IC0/1 n = 44
OS Median OS
(range) Not reached (1 to 20+ mo)
8 mo (1 to 15+ mo)
1-y survival (95% CI)
57% (41-73)
38% (19-56)
IC2/3
IC0/1
Cancer immunotherapy Roche program update Atezolizumab in lung cancer Atezolizumab in bladder cancer
Targeted therapies and combinations
Alectinib in ALK-positive lung cancer Cobimetinib + Zelboraf in melanoma Kadcyla, Perjeta, Herceptin in HER2+ breast cancer
Hematology Gazyva in NHL
Agenda Setting new standards, developing combinations
64
Results from P2 US and Global Studies
• Alectinib, next generation, brain penetrant ALK inhibitor
• Two P2 studies (global and US) show high systemic and CNS response rates in crizotinib-failed patients
• Median PFS: 8.9m & 6.3m (global & US study, respectively)
• Good tolerability with minimal dose modifications
• Final duration of response and PFS results expected in H2 2015
Alectinib in ALK+ NSCLC after crizotinib failure Strong efficacy in two phase 2 studies
65
ORR CR
0
10
20
30
40
50
60
70
80
All (n=87)
Measurable CNS disease
(n=16)
All (n=122)
Measurable CNS disease
(n=16)
US Study Global Study
46%
69%
50% 57%
13% 20%
All (n=69)
Ou S-H. et al, ASCO 2015; Gandhi L. et al, ASCO 2015
Overall and CNS Response Rates
• Both global and US studies show high ORR (57-69%) in measureable CNS disease; disease control rates 80-100%
• Median duration of response in measureable CNS disease was 10.3 months in the global study
• Filing planned 2015
• Global phase III study in 1L ALK+ NSCLC (Alex) on-going: alectinib vs crizotinib
Alectinib in ALK+ NSCLC after crizotinib failure Excellent CNS disease control
66
Measureable CNS responses in global study
Day 6 Day 87
Ou S-H. et al, ASCO 2015; Gandhi L. et al, ASCO 2015
• Median PFS of ~1 year in Cobimetinib + Zelboraf arm with longer follow-up (14.2 m) • OS data not yet mature • Filed in US and EU
Cobimetinib+Zelboraf in Melanoma (coBRIM) Update confirms benefit in BRAFV600+ patients
67
Progression free survival
Orphan disease designation
ORR = overall response rate; CR = complete response; PR = partial response; DoR = duration of response Larkin J. et al, ASCO 2015
HR = 0.58 (0.46-0.72)
12.3m 7.2m
Zelboraf + Cobimetinib
(n = 247)
Zelboraf + Placebo
(n = 248)
% ORR 69.6 50.0
% CR 15.8 10.5
Median PFS 12.3 7.2
Median DoR in months 13.0 9.2
Cobimetinib+Zelboraf in Melanoma (BRIM7) Phase I update shows strong efficacy
68
• Two-year survival rate demonstrates benefit of cobimetinib + Zelboraf
• Projected 28.5 m median OS compares to historical 13.6 m with Zelboraf alone
• Results show importance of combination vs sequential use of targeted therapy in melanoma
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease Pavlick A. et al, ASCO 2015
Vem prog Naive
Time (months) 1 5 9 13 17 21 25 29 33 37
Zelboraf Progressors (N=66) BRAF inhibitor
−naive (n=63)
Zelboraf-Progressors
(n=66)
ORR% 87.3 15.2
CR% 15.9 1.5
mPFS (m) 13.8 2.8
mOS (m) 28.5 8.4
1-yr OS% 82.5 34.7
2-yr OS% 61.1 15.1
Overall survival
Kadcyla + Perjeta in 1L HER2+ mBC (MARIANNE) Non-inferior PFS for Kadcyla or Kadcyla + Perjeta
69
• K and K + P achieved non-inferiority but not superiority to H + T
• Addition of Perjeta to Kadcyla did not improve PFS
• Kadcyla was better tolerated and maintained health-related quality of life for a longer duration
Herceptin + docetaxel (H+T) (8 mg/kg LD then 6 mg/kg + 100 or 75 mg/m2 q3w)
OR Herceptin + paclitaxel (H+T)
(4 mg/kg LD then 2 mg/kg + 80 mg/m2 qw)
Kadcyla + placebo (K) (3.6mg/kg + 840 mg LD then 420 mg q3w)
Kadcyla + Perjeta (K+P) (3.6mg/kg + 840 mg LD then 420 mg q3w)
Previously untreated
HER2+mBC n=1092
Ellis P. et al, ASCO 2015
Median PFS (m)
HR vs H+T
HR vs
K
13.7
14.1
15.2
0.91 p=0.31
0.87 p=0.14
0.91
1:1:1
Perjeta + Herceptin + docetaxel
Perjeta + Herceptin in HER2+ eBC (NEOSPHERE) 5yr follow-up shows lasting benefit in neoadjuvant setting
70
• PFS and DFS benefit of neoadjuvant Perjeta + Herceptin + docetaxel - despite identical adjuvant therapy
• No new safety concerns with longer follow-up
• APHINITY adjuvant study results in 2016
FEC = 5-fluorouracil, Epirubicin, Cyclophosphamide; pCR = pathologic complete response; PFS = progression free survival; DFS = disease free survival Gianni L. et al, ASCO 2015 * PT arm also received docetaxel q3w X 4
Herceptin+docetaxel (H+T) n=107
Perjeta+Herceptin+docetaxel (P+H+T)
n=107
Perjeta+Herceptin n=107
Perjeta+docetaxel n=96
neoadjuvant
FEC q3 w x 3* + Herceptin
adjuvant
PFS, DFS pCR
S U R G E R Y
P + H + T (n=107)
H + T (n=107)
Events PFS 17 19
5-year PFS 86% 81%
HR 0.69 (0.34-1.40)
Events DFS 15 (14.9%) 18 (17.5%)
5-year DFS 84% 81%
HR 0.60 (0.28-1.27)
• Achievement of tpCR (ITT analysis of all patients) reduced risk of PFS (HR = 0.54)
• Results support pCR as an earlier indicator of benefit
pCR endpoint
HER2 franchise outlook Complete portfolio of innovative drugs
71
2017
Established standard of care New standard of care Trials in progress
Adjuvant BC
Herceptin + chemo
Herceptin sc + chemo (HannaH)
Herceptin & Perjeta + chemo (APHINITY)
1st line mBC
Herceptin + chemo
Herceptin & Perjeta + chemo (CLEOPATRA)
2nd line mBC Xeloda + lapatinib Kadcyla (EMILIA)
2016 2012 2013 2014 2015 2011 2019 2018 2020
Kadcyla (KATHERINE) Kadcyla & Perjeta (KAITLIN)
Biosimilar launch (EU)
Neoadjuvant BC
Herceptin + chemo (NOAH)1
Herceptin & Perjeta + chemo (Neosphere, Tryphaena)
Kadcyla & Perjeta (KRISTINE)
Kadcyla & Perjeta (MARIANNE)
• APHINITY, KRISTINE results in 2016
• NEOSPHERE update ASCO 2015
72
Cancer immunotherapy Roche program update Atezolizumab in lung cancer Atezolizumab in bladder cancer
Targeted therapies and combinations
Alectinib in ALK-positive lung cancer Cobimetinib + Zelboraf in melanoma Kadcyla, Perjeta, Herceptin in HER2+ breast cancer
Hematology Gazyva in NHL
Agenda Setting new standards, developing combinations
Hematology franchise A broad portfolio of innovative drugs
73
* venetoclax in collaboration with AbbVie BR = bendamustine+Rituxan venetoclax (Bcl2 inhibitor); polatuzumab vedotin (CD79b ADC)
Biosimilars delayed to 2017
Breakthrough therapy designation for venetoclax
in R/R CLL 17p
Compound Combination Indication P 1 P 2 P 3
Gazyva +chemo GREEN CLL
Gazyva +chemo GOYA aNHL
Gazyva +chemo GADOLIN iNHL
Gazyva +chemo GALLIUM 1L FL
Gazyva +aPD-L1 R/R FL
Gazyva +aPD-L1 aNHL
venetoclax* +Rituxan MURANO R/R CLL
venetoclax +Gazyva CLL14 CLL
venetoclax R/R CLL 17p
venetoclax +Rituxan/+BR R/R FL
venetoclax +Rituxan/Gazyva+chemo 1L aNHL
venetoclax +BR R/R NHL
venetoclax +bortezomib+chemo R/R MM
venetoclax +chemo AML
polatuzumab +Rituxan/Gazyva ROMULUS NHL
polatuzumab +Gazyva/BR R/R FL
polatuzumab +Gazyva/BR aNHL
Data presented at ASCO
Second positive readout for Gazyva GADOLIN in Rituxan-refractory iNHL
74
Rituxan + CHOP
Gazyva + CHOP Front-line DLBCL
(aggressive NHL) n=1418
PFS Trial to continue until 2016
Rituxan q2mo x 2 years
Gazyva q2mo x 2 years
Rituxan + CHOP or Rituxan or Rituxan + bendamustine
CR, PR
Gazyva + CHOP or Gazyva + CVP or
Gazyva + bendamustine 1L iNHL n=1401
Induction Maintenance
PFS Enrollment complete Q1 2014 Data expected 2017
GOYA: Ph III 1L Diffuse Large B-cell Lymphoma (DLBCL)
GALLIUM: Ph III 1L Indolent NHL (iNHL)
In collaboration with Biogen Idec CHOP=Cyclophosphamide, Doxorubicin, Vincristine and Prednisone; CVP=Cyclophosphamide, Vincristine and Prednisolone
CLL11: Ph III Chronic Lymphocytic Leukemia (CLL)
chlorambucil
Rituxan + chlorambucil
Gazyva + chlorambucil 1L CLL n=781
PFS Approved in Q4 2013
Primary end-point:
GADOLIN: Ph III Recurrent Indolent NHL (iNHL)
Gazyva q2mo x 2 years
CR, PR, SD
bendamustine Rituxan-refractory iNHL
n=411
Induction Maintenance PFS Data at ASCO 2015 Gazyva + bendamustine
Gazyva in Rituxan-refractory iNHL (GADOLIN) Significant PFS improvement achieved
75
• PFS significantly prolonged by independent (HR=0.55) and investigator (HR 0.52) assessment • Median PFS was ~ doubled by investigator assessment (29 versus 14 months) • OS data immature • Filing planned in 2015
14.9m
not reached
IFR-assessed PFS
a = Stratified HR Sehn L. et al, ASCO 2015
OS
HRa = 0.55 (0.40-0.74)
Setting new standards, developing combinations Driven by the breadth of our portfolio
76
venetoclax
alectinib cobimetinib
CSF-1R
CEA-IL2v
anti-OX40
anti-CD40
IDO/TDO
CEA-CD3
Targeted combinations approved Chemotherapy combinations approved Roche combinations in trials Chemotherapy combinations in trials
NMEs to be filed soon
Launched portfolio
Immunotherapy portfolio
atezolizumab
chemo
Growing importance of molecular information in cancer immunotherapy
77
Garret Hampton, Ph.D. Vice President, Oncology Biomarker Development and Companion Diagnostics
Personalized healthcare A cornerstone of our strategy
78
> 60% of current drugs in our development portfolio have a companion diagnostic
Diagnostics Pharma
Right patient – right drug
4 of 5 BTD were enabled by
having a Dx that identified patients most
likely to benefit
Molecule Dx
Gazyva CLL
Alectinib ALK+ NSCLC
Atezolizumab PD-L1+ NSCLC
Atezolizumab PD-L1+ UBC
Venetoclax 17p- CLL
Oncology is evolving More complex science with better patient outcomes
79
Overall survival in EGFR mut+ lung cancer Disease heterogeneity in lung cancer
Time (months) 0 3 6 9 12 15 18 21 24 27 30 33 36
0
0.2
0.4
0.6
0.8
1.0
PFS
prob
abili
ty
Erlotinib (n = 86) Chemotherapy (n = 87) HR 0.37 (95% CI 0.25–0.54);
log-rank p < 0.0001
86 63 54 32 21 17 9 7 4 2 2 0 0 87 49 20 8 5 4 3 1 0 0 0 0 0
Erlotinib Chemo
Number at risk
Unknown
MET splice site MET
Amplification
KRAS NRAS
ROS1 Fusions
KIF5B-RET
EGFR
ALK Fusions
HER2 BRAF
PIK3CA AKT1 MAP2K1
PD-L1 expression
Rosell et al. (2012) The Lancet
Biomarker discovery and development at Genentech/Roche
80
Disease Technology
Therapeutics
• Biomarker prevalence • Prognostic significance • Subsets of unmet need • Pipeline opportunities • Dx hypotheses
Understand disease biology
Identify biomarkers
• Pharmacodynamic • Predictive • Response surrogate • Resistance (innate/acquired)
Define diagnostic endpoints
• Companion Dx endpoints • Response surrogates
• Multiplex assays • Real-time Dx • Monitoring
Develop new technologies
Predictive markers – tissue staining for PD-L1 Cancer and/or immune cell expression of PD-L1 can correlate with clinical benefit
81
PD-L1+ (immune cells)
PD-L1+ (tumor cells)
Tumor type n % of PD-L1–positive (immune cells)
% of PD-L1–positive (tumor cells)
NSCLC 184 26 24
RCC 88 25 10
Melanoma 59 36 5
HNSCC 101 28 19
Gastric 141 18 5
CRC 77 35 1
Pancreatic 83 12 4
Bladder cancer 205 27 11
Herbst et al (2014) Nature
Patient selection enriches for benefit PD-L1-selected lung (TC & IC) and bladder cancer (IC)
82
PD-L1 IC staining Score IC ≥ 10% IC3
IC ≥ 5% and < 10% IC2 IC ≥ %1 and < 5% IC1
IC < 1% IC0
PD-L1 TC staining Score TC ≥ 50% TC3
TC ≥ 5% and < 50% TC2 TC ≥ 1% and < 5% TC1
TC < 1% TC0
Bladder cancer: Overall survival*
Time (months)
Ove
rall
surv
ival
0 3 6 8 11 12 19 0
20
40
60
80
100
1 2 4 5 7 9 10 13 14 15 16 17 18 20 21
Median OS 7.6 mo (95% CI, 4.7-NE)
Median OS Not Reached (95% CI, 9.0-NE)
IC2/3
IC0/1
+ Censored
Lung cancer: Survival hazard ratio*
0.1 1
In favor of docetaxel
0.77
1.12
0.63
0.56
0.46
Hazard Ratioa
In favor of atezolizumab
TC3 or IC3
TC2/3 or IC2/3
TC1/2/3 or IC1/2/3
TC0 and IC0
ITT (N = 287)
0.2 1 2
* Monotherapy data
Using patient data to understand cancer immunity-cycle
83
Atezolizumab Phase 1 data: Urothelial bladder cancer patients
Progressive disease (PD) Why do many patients not respond? • No pre-existing immunity?
Cha
nge
in s
um o
f lon
gest
dia
met
ers
(SLD
) fr
om b
asel
ine
(%)
100 80 60 40 20 0
-20 -40 -60 -80
-100 0 21 42 63 84 105 126 147 168 189 210 231 252 273 294
Time on study (days)
Complete response Partial response Stable disease Progressive disease
Monotherapy durable responses (PR/CR) What are the drivers of single agent response? How can PRs be enhanced to CRs? • Insufficient T cell immunity? • Multiple negative regulators?
Stable disease (SD) What combinations will promote PRs & CRs? • Insufficient T cell immunity? • Multiple negative regulators?
Powles et al., Nature 2014
Biomarker discovery and development Integral part of the cancer immunotherapy learning organization
84
Research (gRED, pRED, Chugai & external)
Development (early and late)
Clinical Insights & Biomarkers
(internal and external)
Partnering (Genentech and Roche)
Cancer Immunotherapy Committee
Combination with Avastin Increasing response rates by keeping cancer immunity-cycle turning
85
Chen & Mellman (2013) Immunity
Anti-VEGF
Patie
nt 1
On-treatment biopsies show absence of T cells in tumor bed before and after treatment with PD-L1
Lack of T cell infiltration may limit response to checkpoint inhibitors
Pre-treatment
Herbst et al. (2014) Nature
On-treatment (week 6)
CD8
Patie
nt 2
CD8
CD8 CD8
Combination with Avastin Increased T cell infiltration and clinical activity
86
CD
31
(vas
cula
ture
) C
D8
(T
cel
ls)
Pre-treatment Avastin Avastin + aPD-L1
Combination regimen benefits most patients irrespective of PD-L1 status
On-treatment biopsies show increased infiltrate and reduction in tumor vasculature
Chan
ge in
sum
of l
arge
st d
iam
eter
s fro
m b
asel
ine
(%)
Time on study (days)
PR SD PD
100 90 80 70 60 50 40 30 20 10
0 -10 -20 -30 -40 -50 -60 -70 -80 -90
-100
IHC 3
IHC 0 IHC 0
IHC 1
IHC 1 IHC 0 IHC 0 IHC 1
IHC 0
0 42 84 126 168 210 252 294 336 378
Discontin.
Sznol et al. ASCO GU 2015
Phase 2 in RCC ongoing (n= 300); Phase 3 initiated
Clinical data guides combinations Identifying potentially synergistic combinations
87
Anti-CSF-1R
Anti-PD-L1
Tumor associated macrophages
Complementary mechanisms of action to enhance benefit from immunotherapies
Myeloid signature associated with lack of response to atezolizumab in bladder cancer
Boxplot of Te↵, Th2 and Myeloid signature by response group. Red: PD; Black: SD; Blue: CR/PR.
●
●
PD SD CR/PR
−6−4
−20
Teff signature
Expression
N=23 N=20 N=15
●
●
●
●
●
●
●
●
●
●
●
●●
●●●
●
●
●
●
●
●
●
●
●
●
●●●
●
●●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●●
●
●
●
PD SD CR/PR
−18
−16
−14
−12
−10
Th2 signature
Expression
N=23 N=20 N=15
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●●
●
●
●●
●
●
●
●
●
●
●
●●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●●
●
●
●
●
●
●
●●
●
PD SD CR/PR
−20
24
Myeloid signature
Expression
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●●●
●
●
●
●
●
●
●
●
●●
●
●
●
●
●
●●
●
●
●●●
●
●
●
●
●
●
●
N=23 N=20 N=15
30
Myeloid signature: IL1B, IL8, CCL2
P=0.01
−2 −1.6 −0.67 0.22 1.1 1.6 2
2 1 0 -1 -2
cbind(1:nc)
Indication
Mel
anom
a
SCC
NSC
LC
RC
C
Aden
oN
SCLC
Blad
der
TNBC
HER
2+BC
CR
C
HR
+BC
Th17 Signature
Treg Signature
Th2 Signature
Teff Signature
B cell Signature
IB Signature
IFNg Signature
NK cell Signature
APC Signature
Myeloid Signature
Immune marker expression (illustrative)
Progressive disease
Phase I combination study of anti-CSF-1R and atezolizumab ongoing
Roche and FMI will innovate together Exclusive development of immunotherapy panel
88 Schumacher and Schreiber (2015) Science Yadav et al (2014) Nature
Tumor profiling with RNA sequencing
Predictive biomarkers & new combinations
Mutation-load and neo-antigen discovery
Boxplot of Te↵, Th2 and Myeloid signature by response group. Red: PD; Black: SD; Blue: CR/PR.
●
●
PD SD CR/PR
−6−4
−20
Teff signature
Expression
N=23 N=20 N=15
●
●
●
●
●
●
●
●
●
●
●
●●
●●●
●
●
●
●
●
●
●
●
●
●
●●●
●
●●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●●
●
●
●
PD SD CR/PR
−18
−16
−14
−12
−10
Th2 signature
Expression
N=23 N=20 N=15
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●●
●
●
●●
●
●
●
●
●
●
●
●●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●●
●
●
●
●
●
●
●●
●
PD SD CR/PR
−20
24
Myeloid signatureExpression
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●●●
●
●
●
●
●
●
●
●
●●
●
●
●
●
●
●●
●
●
●●●
●
●
●
●
●
●
●
N=23 N=20 N=15
30
Myeloid signature: IL1B, IL8, CCL2 .
P=0.01
−2 −1.6 −0.67 0.22 1.1 1.6 2
2 1 0 -1 -2
cbind(1:nc)
Indication
Mel
anom
a
SCC
NSC
LC
RC
C
Aden
oN
SCLC
Blad
der
TNBC
HER
2+BC
CR
C
HR
+BC
Th17 Signature
Treg Signature
Th2 Signature
Teff Signature
B cell Signature
IB Signature
IFNg Signature
NK cell Signature
APC Signature
Myeloid Signature
Immune marker expression (illustrative)
Progressive disease
Identifying immunogenic mutations by structure-guided algorithms
Our vision for cancer immunotherapy A personalized approach to treatment
89 *Hypothetical algorithm
*Evaluate tumor: Is the tumor inflamed?
1
Strong PD-L1
Tx with aPD-L1/PD-1
2
Weak PD-L1
Are suppressive myeloid cells present?
3
No PD-L1
IDO/kyneurinin expressed?
4 No identifiable immune targets
Chemo+ Atezolizumab
Anti-CSF-1R+ Atezolizumab
IDOi+ Atezolizumab
Are T cells at tumor periphery? MHC loss?
Tumor antigen expression?
No T cells?
Antigen experienced?
1 2 3
Avastin+ Atezolizumab
No identifiable immune targets
Chemo+ Atezolizumab
4
T cell BiSpecific+
Atezolizumab
Anti-OX40+ Atezolizumab
Inflamed Y
Non-Inflamed N
Patient journey tomorrow Bridging comprehensive testing and drug development
90
Clinical decision
Patient care
Comprehensive testing
Molecular monitoring
R&D insights
Summary and Q&A
Karl Mahler Head of Investor Relations, Roche
91
Summary Skin cancer
cobimetinib + Zelboraf: Ph III (coBRIM) in 1L BRAF+ mM; PFS & biomarker update Filed in 2014
cobimetinib + Zelboraf: Ph Ib (BRIM7) in BRAF+ mM; OS update
Lung cancer
alectinib: two Ph II in 2L ALK+ NSCLC Filing in 2015
Atezolizumab (anti-PDL1): POPLAR, COMBO, FIR Discuss filing 2015
Avastin: mesothelioma Discuss filing 2015
Bladder cancer
Atezolizumab (anti-PDL1): Ph I update in bladder Discuss filing 2015
Breast cancer
Kadcyla: Ph II (ADAPT) neoadjuvant 12 weeks HER2+ HR+ BC
Kadcyla + Perjeta: Ph III (MARIANNE) in 1L HER2+ mBC
Herceptin + Perjeta: Ph II (NEOPSPHERE) in neoadjuvant HER2+ BC Approved in US, filed in EU
Avastin + Letrozole: Ph III (CALGB40503) in 1L HR+ mBC
Hematology
Gazyva: Ph III (GADOLIN) in R/R iNHL Filing 2015
Venetoclax: Ph I in R/R NHL and R/R MM BTD: Filing 2015 in 17p CLL depleted
92
Cancer immunotherapy: Encouraging early data in monotherapy across various cancer types
93
NSCLC 2L ORR range mPFS range mOS* range Prevalence
Un-stratified ~ 15% ~ 3 m ~ 9-11 m
Stratified 40-45% ~ 6-8 m Not reached ~20-30%
* Comparisons based on publicly available competitor data sets. Significant limitations with these cross-trial comparisons; significant variability in baseline population demographics further limit conclusions Note: CheckMate 057 2L+ non-squamous NSCLC trial was stopped early because the study met its OS endpoint
Bladder 2L ORR range mPFS range mOS range Prevalence
Stratified 25-45% ~ 2-5.5 m Not reached ~30%
Range across various studies
Range across various studies
Cancer immunotherapy: Still many open questions
94
to (step 4) and infiltrate the tumor bed (step 5), specifically recog-nize and bind to cancer cells through the interaction between itsT cell receptor (TCR) and its cognate antigen bound to MHCI(step 6), and kill their target cancer cell (step 7). Killing of the can-cer cell releases additional tumor-associated antigens (step 1again) to increase the breadth and depth of the response in sub-sequent revolutions of the cycle. In cancer patients, the Cancer-Immunity Cycle does not perform optimally. Tumor antigensmaynot be detected, DCs and T cells may treat antigens as self ratherthan foreign thereby creating T regulatory cell responses ratherthan effector responses, T cells may not properly home totumors, may be inhibited from infiltrating the tumor, or (mostimportantly) factors in the tumor microenvironment might sup-press those effector cells that are produced (reviewed by Motzand Coukos, 2013).
The goal of cancer immunotherapy is to initiate or reinitiate aself-sustaining cycle of cancer immunity, enabling it to amplifyand propagate, but not so much as to generate unrestrainedautoimmune inflammatory responses. Cancer immunotherapiesmust therefore be carefully configured to overcome the negativefeedback mechanisms. Although checkpoints and inhibitors arebuilt into each step that oppose continued amplification and can
dampen or arrest the antitumor immune response, the mosteffective approaches will involve selectively targeting the rate-limiting step in any given patient. Amplifying the entire cyclemay provide anticancer activity but at the potential cost ofunwanted damage to normal cells and tissues. Many recent clin-ical results suggest that a common rate-limiting step is the im-munostat function, immunosuppression that occurs in the tumormicroenvironment (Predina et al., 2013; Wang et al., 2013).Initiating Anticancer Immunity: Antigen Release,Presentation, and T Cell PrimingAttempts to activate or introduce cancer antigen-specific T cells,as well as stimulate the proliferation of these cells over the last 20years, have led to mostly no, minimal or modest appreciableanticancer immune responses. The majority of these effortsinvolved the use of therapeutic vaccines because vaccines canbe easy to deploy and have historically represented an approachthat has brought enormous medical benefit (reviewed by Pal-ucka and Banchereau, 2013). Yet, cancer vaccines were limitedon two accounts. First, until recently, there was a general lack ofunderstanding of how to immunize human patients to achievepotent cytotoxic T cell responses. This limitation reflectscontinued uncertainties concerning the identities of antigens to
Figure 1. The Cancer-Immunity CycleThe generation of immunity to cancer is a cyclic process that can be self propagating, leading to an accumulation of immune-stimulatory factors that in principleshould amplify and broaden T cell responses. The cycle is also characterized by inhibitory factors that lead to immune regulatory feedback mechanisms, whichcan halt the development or limit the immunity. This cycle can be divided into seven major steps, starting with the release of antigens from the cancer cell andending with the killing of cancer cells. Each step is described above, with the primary cell types involved and the anatomic location of the activity listed. Ab-breviations are as follows: APCs, antigen presenting cells; CTLs, cytotoxic T lymphocytes.
2 Immunity 39, July 25, 2013 ª2013 Elsevier Inc.
Immunity
Review
How can we convert unresponsive tumors into responsive tumors?
Can we modulate / monitor T-cell responses?
What are the factors affecting T-cell infiltration?
Can we create a personalized immunotherapy paradigm?
Can we convert an unresponsive tumor to a responsive one?
What influences durability of response?
Immunosuppression
T Cell Trafficking
Antigen Presentation
Biology
Biomarker/ Tools
Indication/ Patient pop.
Therapy Efficacy/ Safety
Doing now what patients need next